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Primary Immunodeficiencies: A&Nbsp;Rapidly Evolving Story

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Primary Immunodeficiencies: A&Nbsp;Rapidly Evolving Story Primary immunodeficiencies: A rapidly evolving story Nima Parvaneh, MD,a,b Jean-Laurent Casanova, MD, PhD,c,d Luigi Daniele Notarangelo, MD, PhD,e,f and Mary Ellen Conley, MDg,h Tehran, Iran, New York, NY, Paris, France, Boston, Mass, and Memphis, Tenn The characterization of primary immunodeficiencies (PIDs) in human subjects is crucial for a better understanding of the Abbreviations used biology of the immune response. New achievements in this field ADAM17: A disintegrin and metalloproteinase 17 have been possible in light of collaborative studies; attention BCR: B-cell receptor paid to new phenotypes, infectious and otherwise; improved EV: Epidermodysplasia verruciformis immunologic techniques; and use of exome sequencing HHV6: Human herpesvirus 6 HPS: Hermansky-Pudlak syndrome technology. The International Union of Immunological Societies HPV: Human papilloma virus Expert Committee on PIDs recently reported on the updated HSE: Herpes simplex virus encephalitis classification of PIDs. However, new PIDs are being discovered HSV1: Herpes simplex virus 1 at an ever-increasing rate. A series of 19 novel primary defects ICA: Isolated congenital asplenia of immunity that have been discovered after release of the ICL: Idiopathic CD41 lymphopenia International Union of Immunological Societies report are IL-36Ra: IL-36 receptor antagonist discussed here. These new findings highlight the molecular ISG15: Interferon-stimulated gene 15 pathways that are associated with clinical phenotypes and IUIS: International Union of Immunological Societies suggest potential therapies for affected patients. (J Allergy Clin LCK: Lymphocyte-specific protein tyrosine kinase Immunol 2013;131:314-23.) LRBA: LPS-responsive beige-like anchor MCM4: Minichromosome maintenance complex component 4 Key words: Primary immunodeficiencies, combined immunodefi- MSMD: Mendelian susceptibility to mycobacterial disease ciencies, well-defined syndromes with immunodeficiency, predomi- MST: Mammalian Ste20-like kinase k nantly antibody defects, defects of immune dysregulation, NEMO: NF- B essential modulator NF-kB: Nuclear factor kB congenital defects of phagocytes, defects in innate immunity, autoin- NK: Natural killer flammatory disorders, mutation detection PI3K: Phosphoinositide 3-kinase PID: Primary immunodeficiency Discuss this article on the JACI Journal Club blog: www.jaci- PLCg2: Phospholipase Cg2 online.blogspot.com. RHOH: Ras homolog gene family member H TBK1: TANK-binding kinase 1 TCR: T-cell receptor Known primary immunodeficiencies (PIDs) include individu- TLR3: Toll-like receptor 3 ally rare but collectively diverse genetic defects that influence TRIF: Toll/IL-1 receptor domain–containing adaptor inducing IFN-b UNC119: Uncoordinated 119 From athe Pediatric Infectious Diseases Research Center and bthe Research Center for WASP: Wiskott-Aldrich syndrome protein Immunodeficiencies, Children’s Medical Center, Tehran University of Medical WIP: WASP-interacting protein Sciences, Tehran; cSt Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York; dthe Laboratory of Human Ge- netics of Infectious Diseases, Necker Branch, Necker Medical School, University Paris Descartes and INSERM U980, Paris; ethe Division of Immunology and fthe Manton Center for Orphan Disease Research, Children’s Hospital Boston, Harvard Medical the development, function, or both of immunity. Taken in a broad School, Boston; gthe Department of Pediatrics, University of Tennessee College of sense, these disorders encompass both the hematopoietic and h Medicine, Memphis; and Le Bonheur Children’s Hospital, Memphis. nonhematopoietic arms of host defense. They result in a wide Disclosure of potential conflict of interest: J.-L. Casanova has received grants from the National Institutes of Health (NIH); has been a consultant for Pfizer, GlaxoSmith- range of clinical symptoms, including but not limited to suscep- Kline, NovImmune, Biogenldec, Merck, and Sanofi-Aventis; and has grants/grants tibility to infections, autoimmunity, inflammation, allergy, and 1 pending from Pfizer and Merck. L. D. Notarangelo is a board member for the Immune malignancy. Significant progress in the field has recently accel- Disease Institute, is employed by Children’s Hospital Boston, has grants/grants erated thanks to collaborative work around the world; improved pending with the NIH, the March of Dimes, and the Jeffrey Modell Foundation; techniques to analyze leukocyte subsets; attention paid to new and has received payment for lectures, including service on speakers’ bureaus for the WAS foundation. M. E. Conley is employed by the University of Tennessee, phenotypes, such as infections selectively caused by certain 2 has received grants/grants pending from the NIH and the March of Dimes, has re- pathogens in otherwise healthy children ; and use of high- ceived payment for lectures from the Immune Deficiency Foundation, and is receiving throughput next-generation sequencing technology (eg, whole- royalties from the Southern Bio for monoclonal antibodies. N. Parvaneh declares no exome sequencing).3 The International Union of Immunological relevant conflicts of interest. Received for publication October 2, 2012; revised November 6, 2012; accepted for pub- Societies (IUIS) Expert Committee on PIDs published the bien- lication November 29, 2012. nial update of the classification of PIDs in a recent article dated 4 Corresponding author: Nima Parvaneh, MD, Pediatric Infectious Diseases Research Cen- November 2011. However, the continuously growing number ter, Children’s Medical Center, 62 Gharib St, 14194 Tehran, Iran. E-mail: nparvaneh@ and variety of PIDs make this type of classification difficult tums.ac.ir. and perhaps calls for a revised approach.5,6 In this review we 0091-6749/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology focus on the 19 new PIDs that appeared in the literature after http://dx.doi.org/10.1016/j.jaci.2012.11.051 the release of the last IUIS report. Some of these reports include 314 J ALLERGY CLIN IMMUNOL PARVANEH ET AL 315 VOLUME 131, NUMBER 2 only a single case, making it difficult to confidently predict the there is a clear keratinocyte phenotype13 but only mild T-cell clinical phenotype; however, each new disorder provides valu- anomalies in EVER-deficient patients.14 A recent study explored able insights into the pathways that normally ensure host defense the genetic basis of an EV-like phenotype in 2 French siblings from environmental challenges while not harming the host. We with persistent cutaneous EV-HPV infections and other clinical classify these new PIDs according to the latest IUIS classi- manifestations, including bronchopulmonary disease and Burkitt fication (Table I). lymphoma in one of them, indicating that the phenotypic spec- trum of the disease is not restricted to susceptibility to HPV.15 Therefore this condition is related to but distinct from EV. The COMBINED IMMUNODEFICIENCIES patients were homozygous for a nonsense allele of the Ras T-cell receptor a gene mutation: T-cell receptor ab1 homolog gene family member H (RHOH), which encodes an T-cell depletion atypical Rho GTPase (RHOH) expressed predominantly in he- T cells comprise 2 distinct lineages that express either ab or gd matopoietic cells. RHOH is crucial for pre-TCR and TCR signal- T-cell receptor (TCR) complexes that perform different tasks in ing and has a role during b-selection and positive selection in the immune responses. During T-cell maturation, the precise order thymus.16,17 The patients displayed a lack of circulating naive and efficacy of TCR gene rearrangements determine the fate of T cells, a lower than normal proportion of skin-homing b71 the cells.7 Productive b-chain gene rearrangement produces a pre- T cells, and impaired TCR signaling. The combination of these TCR on the cell surface in association with pre-Ta invariant T-cell defects might explain the pathogenesis of susceptibility peptide (b-selection). Pre-TCR signals promote a-chain recombi- to cutaneous EV-HPVs. EV-like features were also recently nation and transition to a double-positive stage (CD41CD81).8 reported in a child with mammalian Ste20-like kinase (MST) This is the prerequisite for central tolerance achieved through pos- 1 deficiency (described below).18 itive and negative selection of thymocytes. Additional insight into the development of TCRab1 T cells was provided by the character- ization of 2 patients from 2 unrelated Pakistani families who had the MST1 deficiency: Loss of naive T cells same homozygous mutation in the TCRa constant (TRAC)gene New insight into the role of MST1 as a critical regulator of and shared increased susceptibility to infections, autoimmunity, T-cell homing and function was provided by the characterization and profound T-cell proliferative impairments but apparently had of 8 patients from 4 unrelated families who had homozygous normal antibody responses.9 One of the cases showed predisposi- nonsense mutations in STK4, the gene encoding MST1.18-20 tion to herpes virus infections (including protracted varicella zoster MST1 was originally identified as an ubiquitously expressed and chronic EBV/HHV6 viremia) and chronic lung disease. In ad- kinase with structural homology to yeast Ste20.21 MST1 is the dition to immunodeficiency, both children had evidence of immune mammalian homolog of the Drosophila Hippo protein, control- dysregulation with a combination of eosinophilia, vitiligo, alopecia ling cell growth, apoptosis, and tumorigenesis.22 It has both areata, autoimmune
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